The present invention concerns a process for the preparation of 2-amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-c]pyrimidine.
U.S. Pat. No. 5,858,924 describes certain substituted benzenesulfonamide compounds and their use as herbicides. 2-Amino-5,8-dimethoxy[1,2,4]triazolo-[1,5-c]pyrimidine is a useful intermediate for the preparation of certain of these herbicides.
In U.S. Pat. No. 5,858,924, 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine is prepared from 3-amino-8-methoxy-5-methylthio[1,2,4]triazolo-[4,3-c]pyrimidine by treatment with ethyl acrylate and sodium methoxide in methanol. The 3-amino-8-methoxy-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine in turn is prepared from 5-methoxy-4-chloro-2-methylthio-pyrimidine by treatment with hydrazine followed by cyclization with cyanogen bromide. It would be advantageous to produce 2-amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-c]pyrimidine more efficiently and in higher yield. It would also be advantageous to avoid the use of methylthio containing intermediates and the use of ethyl acrylate in the rearrangement of a [1,2,4]triazolo[4,3-c]pyrimidine into a [1,2,4]-triazolo[1,5-c]pyrimidine.
The present invention concerns the preparation of 2-amino-5,8-dimethoxy[1,2,4]triazolo-[1,5-c]pyrimidine from a 5-chloro or 5-methoxy substituted 3-amino-8-methoxy[1,2,4]triazolo[4,3-c]-pyrimidine. More particularly, the present invention concerns a process for the preparation of a compound of the formula 
which comprises contacting a 3-amino-8-methoxy-[1,2,4]triazolo[4,3-c]pyrimidine of the formula 
wherein Z represents Cl or OCH3 with sodium or potassium methoxide in an alcohol solvent.
Another aspect of the present invention concerns a process for the preparation of 
which comprises the steps of:
a) contacting a 5-methoxy-4-chloropyrimidine of the formula 
xe2x80x83wherein Z represents Cl or OCH3 with hydrazine and a base to prepare a 5-methoxy-4-hydrazinopyrimidine of the formula 
xe2x80x83wherein Z is as previously defined;
b) contacting the 5-methoxy-4-hydrazinopyrimidine with cyanogen chloride or cyanogen bromide to prepare a 3-amino-8-methoxy[(1,2,4]triazolo[4,3-c]pyrimidine of the formula 
xe2x80x83wherein Z is as previously defined; and
c) contacting the 3-amino-8-methoxy[1,2,4]triazolo-[4,3-c]pyrimidine with sodium or potassium methoxide in an alcohol solvent.
The rearrangement of the 3-amino-8-methoxy-[1,2,4]triazolo[4,3-c]pyrimidine of the formula 
wherein Z represents Cl or OCH3 to 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]-pyrimidine is accomplished by treatment with sodium methoxide or potassium methoxide in an alcohol solvent.
For Z represents OCH3, only a catalytically effective amount of methoxide is required, e.g., from about 0.01 to about 0.5 equivalents of methoxide per mole of [1,2,4]triazolo[4,3-c]pyrimidine. However, since the rate is dependent on the concentration of methoxide, the use of about 0.1 to about 0.5 equivalents of methoxide is usually preferred.
For Z represents Cl, an additional equivalent of methoxide is required to concomitantly convert the chloro substituent to a methoxide substituent. Thus, in this case, from about 1.1 to about 1.5 equivalents of methoxide is preferred.
The rearrangement is generally conducted in methanol as the solvent. Other primary and secondary alcohols may be used, however, depending on the reaction conditions, a significant amount of alkoxide exchange may occur at the 5-position of the triazolo-pyrimidine. Sterically hindered alcohols, for example tertiary-alcohols like t-butanol and t-amyl alcohol, may be used as the solvent resulting in little or no alkoxide exchange. Nevertheless, methanol is usually the preferred solvent. It is also possible to perform the rearrangement in the presence of additional diluents provided those diluents do not interfere with the desired reaction and are chemically inert to the reactants, particularly the methoxide base. A particularly suitable additional diluent is acetonitrile, which is often used as the solvent in the preparation of the [1,2,4]triazolo[4,3-c]-pyrimidine.
The rearrangement is conducted at a temperature from about 0xc2x0 C. to the reflux temperature of the alcohol solvent. Temperatures from about 10xc2x0 C. to about 35xc2x0 C. are usually preferred.
The product is isolated by conventional techniques such as by filtration of a precipitated or crystallized material.
In a typical reaction, the 5-chloro or 5-methoxy substituted 3-amino-8-methoxy[1,2,4]triazolo-[4,3-c]pyrimidine is dissolved or suspended in alcohol and treated with the appropriate amount of sodium methoxide in methanol at ambient temperature. After the reaction is complete, the reaction mixture is diluted with water and the precipitated product is collected by filtration and dried. Optionally, some or most of the alcohol may be removed by distillation prior to filtration to improve crystal filtration or reduce solubility of the product in the solvent and therefore improve recovery.
The 5-chloro and 5-methoxy substituted 3-amino-8-methoxy[1,2,4]triazolo[4,3-c]pyrimidines can be conveniently prepared from the corresponding 2,4-dichloro-5-methoxypyrimidine(Chesterfield, J., McOmie, J. F. W., Sayer, E. R., xe2x80x9cPyrimidines. Part VIII. Halogeno- and Hydrazino-pyrimidinesxe2x80x9d J. Chem. Soc. 1955, 3478-3481) and the 2,5-dimethoxy-4-chloro-pyrimidine respectively by a) the reaction with hydrazine and base followed by b) reaction with cyanogen chloride or cyanogen bromide. 
During the reaction with hydrazine in step a), a base is required to neutralize the hydrogen chloride produced. This base may be an additional equivalent of hydrazine itself. However, it is often preferred to use an auxiliary base such as sodium or potassium carbonate, sodium or potassium hydroxide or a trialkylamine. Sodium carbonate is the preferred auxiliary base.
During the reaction with the cyanogen halide in the cyclization step b), hydrogen halide is produced. By using enough additional methoxide as base to neutralize the hydrogen halide given off, it is possible to accomplish both the methoxy substitution and/or the rearrangement as part of the work-up of the cyclization reaction. This process modification advantageously avoids the isolation of the [1,2,4]triazolo[4,3-c]pyrimidine.